Genetic Contribution in Low Back Pain: A Prospective Genetic Association Study.

OBJECTIVES: Chronic pain is one of the most common reasons individuals seek medical attention. It is a major issue because of the wide interindividual variability in the analgesic response. This might be partly explained by the presence of variants in genes encoding molecules involved in pharmacodynamics and pharmacokinetics. The aim was to analyze opioid effectiveness in chronic low back pain (CLBP) relief after opioid titration, unveiling the impact of pharmacogenetics. METHODS: The study included 231 opioid-naïve patients from the Spine Unit; age 63 ± 14 years, 64% female, body mass index 29 ± 6 kg/m2 , visual analog scale pain intensity score 73 ± 16 mm. Clinical data were collected at baseline, 3 months after opioid titration, and after 2 to 4 years of follow-up concerning pain (intensity and relief), quality of life, disability, comorbidities, and drug prescription (opioid dose, rotations, and adverse events). The genotype influence of OPRM1, COMT, UGT2B7, ABCB1, KCNJ6, and CYP3A5*3A in analgesic response was analyzed by reverse-transcription polymerase chain reaction genotyping. RESULTS: Patients with the COMT G472A-AA genotype (rs4680) and KCNJ6 A1032G-A allele (rs2070995) CLBP responded differently to opioid titration, with higher pain intensity requiring higher dosing. Furthermore, GG- genotypes of A118G (OPRM1, rs1799971) and A854G (UGT2B7, rs776746) influenced the neuropathic component. After opioid titration, CLBP intensity, neuropathic component, low back pain disability, anxiety, and depression significantly decreased, while quality of life improved. CONCLUSION: Single-nucleotide polymorphisms in genes involved in pain transmission and opioid metabolism might predispose to exaggerated sensitivity and differences in the opioid analgesic effect in patients with CLBP. We encourage clinical trials for their clinical application in chronic pain management.

ß2­adrenergic receptor functionality and genotype in two different models of chronic inflammatory disease: Liver cirrhosis and osteoarthritis.

The present study was designed to investigate the functional status of ß2 adrenoceptors (ß2AR) in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthritis (OA). The ß2AR gene contains three single nucleotide polymorphisms at amino acid positions 16, 27 and 164. The aim of the present study was to investigate the potential influence of lymphocyte ß2AR receptor functionality and genotype in LC and OA patients. Blood samples from cirrhotic patients (n=52, hepatic venous pressure gradient 13±4 mmHg, CHILD 7±2 and MELD 11±4 scores), OA patients (n=30, 84% Kellgren­Lawrence severity 4 grade, 14% knee replacement joint) and healthy volunteers as control group (n=26) were analyzed. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and basal and isoproterenol induced adenylate cyclase activity (isoproterenol stimulus from 10­9 to 10­4 mM), and ß2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. ß2AR functionality was decreased in the two different models of chronic inflammatory disease studied, OA (50% vs. control) and LC (85% vs. control). In these patients, the strength of the ß2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the ß2AR stimulus is decreased in chronic inflammatory processes including LC and OA, suggesting that the adrenergic system may be important in the development of these processes.

G protein-coupled receptor signalling potentiates the osmo-mechanical activation of TRPC5 channels.

TRPC5 is an ion channel permeable to monovalent and divalent cations that is widely expressed in different tissues. Although implicated in the control of neurite extension and in the growth cone morphology of hippocampal neurons, as well as in fear-related behaviour, the mechanisms by which TRPC5 is activated remain poorly understood. TRPC5 is known to be activated downstream of Gq-coupled receptors and by membrane stretch, and since there is evidence that mechanical stress may directly activate Gq-coupled receptors, we examined the relationship between the activation of TRPC5 by the type 1 histamine receptor and osmotic stress. Using calcium imaging and patch clamp recordings, we found that a higher proportion of cells expressing TRPC5 respond to hypoosmotic solution when they co-express H1R. This response is associated with a phospholipase C-dependent increase in the cells internal calcium concentration, which is abolished on depletion of calcium stores. We also found that the hypoosmotic stimulus that provokes mechanical stress drives the translocation of TRPC5 to the plasma membrane by a mechanism dependent on PI3K. This increase in TRPC5 at the plasma membrane augments the proportion of cells that respond to hypoosmotic stimulation. Together, these results suggest that hypoosmotic cell-swelling activates Gq-coupled receptors, which in turn enhance the activation of TRPC5 by regulating this channel membrane trafficking. Gq-coupled receptors and TPRC5 are co-expressed in several tissues such as those of the vascular system and in somatosensory neurons, suggesting that this mechanism of TRPC5 activation may have interesting and important implications in arterial pressure sensing and mechanotransduction.